Each year in the Indian subcontinent alone, over 500,000 individuals play host to Leishmania donovani, an insidious parasite that invades macrophages, rapidly infiltrates the vital organs and ultimately leads to severe infection of the visceral reticuloendothelial system. Visceral leishmaniasis, also known as Kala-azar, is most prevalent in the weak and the young within a population. Left untreated, almost all infected individuals will die. Visceral leishmaniasis affects over 200 million people from 62 countries. The therapeutic arsenal against Leishmania is limited to a small number of parenterally administered agents, with daily injections of pentavalent antimony compound. Although more expensive than the antimonials, amphotericin B (AmpB) has a 97% cure rate and no reported resistance. However, drug therapy involves IV administration over 30-40 days and is associated with infusion-related side-effects (fever, chills, bone pain, thrombophlebitis). The dose-limiting toxicity, which may even affect the ability to achieve a cure, is renal impairment. In addition, due to the prohibitive cost and difficult route of drug administration, amphotericin B is failing to reach many patients.
In developed nations, disseminated fungal infections such as candidiasis, histoplasmosis, coccidiosis, and aspergillosis are on the rise, affecting patients with cancer, organ transplant recipients, diabetics and those with HIV/AIDS. In these patients, invasive fungal infections may account for as many as 30% of deaths. Despite the development of a number of new antifungal agents, amphotericin B formulated as an IV administered micelle and liposomal dispersion remains one of the most effective agents in the treatment of systemic fungal infections. In addition, a variety of parenteral formulation approaches have been studied for AmpB. While effective, the limitations of these parenteral formulations of amphotericin B are the safety issues associated with administration (infection of the indwelling catheter, patient chills and shaking due to RBC haemolysis, dose-dependent renal toxicity), feasibility of administration of parenteral products in remote locations and high drug cost.
The development of an effective, stable, and safe oral formulation of amphotericin B that would have significant applications in the treatment of disseminated fungal infections and would dramatically expand access to treatment of visceral leishmaniasis. However, the bioavailability of AmpB is negligible due to low aqueous solubility and instability at the low pH found in gastric fluid. Such limitations also apply to a variety of other therapeutic agents for which oral formulations are desirable.
A need exists for effective, stable, and safe oral formulations of amphotericin B as well as many other therapeutic agents that provide for enhanced bioavailability and/or increased stability of the therapeutic agent of interest the low pH found in gastric fluid. The present invention seeks to fulfill these needs and provides further related advantages.